The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor (Meunier et al., Nature 377, 1995, pp. 532-535), which belongs to the family of opioid receptors and can be found in many regions of the brain and spinal cord and has a high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors and the amino acid sequence of the nociceptin peptide bears a marked similarity to those of the known opioid peptides. The activation of the receptor induced by nociceptin leads via the coupling with Gi/o, proteins to an inhibition of adenylate cyclase (Meunier et al., Nature 377, 1995, pp. 532-535).
The nociceptin peptide exhibits after intercerebroventicular application a pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, pp. 792-794). These findings can be interpreted as an inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, pp. 333-337). In this connection an anxiolytic activity of nociceptin was also detected (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
On the other hand, an antinociceptive effect of nociceptin was also found in various animal models, especially after intrathecal application. Nociceptin has an antinociceptive effect in various pain models, for example in the tail flick test in mice (King et al., Neurosci. Lett., 223, 1997, 113-116). An antinociceptive action of nociceptin was likewise detected in models of neuropathic pain, which is particularly interesting since the efficacy of nociceptin increases after axotomy of spinal nerves. This is in contrast to conventional opioids, whose efficacy decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, pp. 9685-9694).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory formation (Manabe et al., Nature, 394, 1997, pp. 577-581), hearing ability (Nishi et al., EMBO J., 16, 1997, pp. 1858-1864) as well as numerous other processes. In a review article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283) a survey is given of the indications or biological processes in which the ORL1 receptor plays a role, or may with a high degree of probability play a rôle. The following inter alia are mentioned: analgesia, stimulation and regulation of food intake, influence on μ agonists such as morphine, treatment of withdrawal symptoms, reduction of the addictive potential of opioids, anxiolysis, modulation of motor activity, memory disturbances, epilepsy; modulation of neurotransmitter secretion, in particular of glutamate, serotonin and dopamine, and concomitant neurodegenerative diseases; influencing of the cardiovascular system, initiation of an erection, diuresis, anti-natriuresis, electrolyte balance, arterial blood pressure, hydropexic disorders, intestinal motility (diarrhoea), relaxing effects on the respiratory pathways and micturition reflex (urinary incontinence). The use of agonists and antagonists as anorectics and analgesics (also in combined administration with opioids) or nootropics is furthermore discussed.
The possible uses of compounds that bind to the ORL1 receptor and activate or inhibit the latter are accordingly multifarious. Apart from this, opioid receptors such as the μ receptor and other sub-types play an important role, specifically in the area of pain treatment, but also in other of the aforementioned medical indications. Accordingly, it is beneficial if a compound also acts on these opioid receptors.